Dendritic cells (DCs) are essential antigen presenting cells for the initiation and control of immune responses. DCs can capture and process antigens, migrate from the periphery to a lymphoid organ, and present the antigens to resting T cells in a major histocompatibility complex (MHC)-restricted fashion. These cells are derived from bone marrow (BM) and display dendritic morphology and high mobility. The discovery of DCs as specialized antigen-presenting cells (APCs) has fueled attempts at DC-based immunization/vaccination strategies that involve targeting DCs for display of specific antigens. Recombinant virus-based vectors have been developed as a mechanism to directly deliver a gene encoding a designated antigen(s) to host cells. Through induction of a desired adaptive immune response, the expressed gene product provides a therapeutic benefit.
Challenges in achieving a safe and effective system include designing a vector that efficiently targets a desired set of host cells, providing a suitable delivery system, and expressing a desired antigen to elicit an effective immune response so that it can be utilized broadly across a designated human subject population.
The envelope glycoproteins of Sindbis virus and other alphaviruses disclosed herein incorporate into the lipid bilayer of the viral particle membrane. Typically, the viral membrane (envelope) includes multiple copies of trimers of two glycoprotein heterodimers, E1 and E2, which are produced from cleavage of a single precursor protein. The precursor protein comprises, from its N- to C-terminus, the E3, E2, 6K and E1 proteins. The small E3 glycoprotein serves as a signal sequence for translocation of the E2 protein into the membrane, and is cleaved from E2 by furin or some other Ca2+-dependent serine proteinase. The 6K protein serves as a signal sequence for translocation of the E1 protein into the membrane and is then cleaved from the precursor protein. WO 2008/011636 and US 2011/0064763 disclose lentiviral packaging systems.